Copper Reactivity Can Be Tuned to Catalyze the Stereoselective Synthesis of 2-Deoxyglycosides from Glycals

Abstract

We demonstrate that tuning the reactivity of Cu by the choice of oxidation state and counterion leads to the activation of both "armed" and "disarmed" type glycals towards direct glycosylation leading to the α-stereoselective synthesis of deoxyglycosides in good to excellent yields. Mechanistic studies show that Cu I is essential for effective catalysis and stereocontrol and that the reaction proceeds through dual activation of both the enol ether as well as the OH nucleophile. Carbohydrates play significant roles in a wide range of biological events 1 and efficient catalytic and asymmetric methods to access this class of chiral molecules are needed to further our understanding of their various roles and functions in health and disease. 2, 3 First row transition metals have recently attracted attention as alternatives to precious metals in catalysis. 4 Among those, copper is a cost-effective, earth-abundant and sustainable metal and Cu-complexes can display unique and versatile reactivity and good functional group tolerance. 4 The chemistry exhibited by Cu can be very diverse depending on its oxidation state, as this metal can efficiently catalyse reactions involving one or twoelectron mechanisms. 4-7 In the context of O-linked glycosylation reactions, a few examples of Cu(II) as a mild oxophilic Lewis acid catalyst for the activation of oxygen-containing leaving groups have been reported. 8-11 More recently, the use of Cu II (OTf)2 as an in situ oxidant in the photoinduced-activation of thioglycosides was also exemplified. 12 However, despite copper catalysts being relatively cheap and widely available, we were surprised by the overall under exploration of this metal in glycosylation chemistry 13-17. Our group is interested in the development of sustainable and catalytic methods for the synthesis of oligosaccharides. 18-21 2deoxy-hexoses are prominent components of natural products which due to the lack of substituents at C-2 to direct the nucleophile approach present significant synthetic challenges and their improved and stereoselective protocols for their assembly has been of great intetest. 5, 18, 22-37 Previous work from our group and others has shown that activation of glycals to yield glycosides can be achieved using transition metals such as Pd(II) 38, 39 , Au(I) 40 or Re(V) 41 catalysts, however activation of sensitive enol ethers bearing electronwithdrawing groups at the C-3 position of the glycal was not possible under those conditions (Scheme 1) and in general harsher conditions used to activate such glycals often lead to donor hydrolysis and/or Ferrier type products. 26 Scheme 1: Cu I-catalysed direct synthesis of deoxyglycosides from glycals

A robust and tunable halogen bond organocatalyzed 2-deoxyglycosylation involving quantum tunneling

“…Specifically, we aim to harness and unravel noncovalent mechanisms unique to XB organocatalysis, so that enabling methodologies, which facilitates the preferential construction of challenging bonds over thiourea catalysis in biologically relevant molecules can be developed. In line with this aim, we have identified the biologically relevant 2-deoxyglycosylation as an ideal reaction model for the discovery for unknown XB catalytic mechanisms [46][47][48][49][50][51][52][53][54][55][56][57][58][59] . The unique poly-oxygenated nature of glycosyl substrates and products provides numerous XB acceptor moieties for the in situ catalytic establishment of dynamic noncovalent activations.…”

“…The unique poly-oxygenated nature of glycosyl substrates and products provides numerous XB acceptor moieties for the in situ catalytic establishment of dynamic noncovalent activations. Moreover, the synthetic importance of 2deoxyglycosides as a privileged and biologically useful compound class is well exemplified by the continual intense interest by many different research groups [46][47][48][49][50][51][52][53][54][55][56][57][58][59] , due to its prevalence in glycosidic natural products, such as digitoxin and saccharomicin B (ref. 46 ).…”

Stereoselective Synthesis of Iminosugar 2-Deoxy(thio)glycosides from Bicyclic Iminoglycal Carbamates Promoted by Cerium(IV) Ammonium Nitrate and Cooperative Brønsted Acid-Type Organocatalysis

“…A range of different promotors for glycal activation were screened aiming to improve the yield of the 2-deoxyiminosugar glycoside targets. These include trifluoroacetic acid (TFA), [(pCF 3 Ph) 3 P–AuCl]/AgOTf, Cu­(OTf) 2 ·C 6 H 6 , B­(C 6 F 5 ) 3 , bis­( p -nitrophenyl) hydrogen phosphate ((O 2 NC 6 H 4 O) 2 P­(O)­OH), ( R )-3,3′-bis­[3,5-bis­(trifluoromethyl)­phenyl]-1,1′-binaphthyl-2,2′-diyl hydrogen phosphate ( 15 ), N , N ′-bis­[3,5-bis­(trifluoromethyl)­phenyl]­thiourea (Schreiner’s thiourea; 16 ), and the combination of (O 2 NC 6 H 4 O) 2 P­(O)­OH or 15 and 16 (see Supporting Information, Table S2) . None of them were effective at mediating the reaction of 1 with octanol.…”

Copper-catalyzed transformation of alkyl nitriles to N-arylacetamide using diaryliodonium salts

“…The interaction of both Cu II and electrogenerated Cu I with a ligand could be assessed by this method, while the low coordinating ability of nitromethane avoided any binding competition issues. 22 MeCN selected as a model substrate 23 displayed only a weak affinity for Cu II but proved to stabilize Cu I due to the formation of a mixture of [Cu I (NCMe) 2 ] + c2 and [Cu I (NCMe) 3 ] + c3 – the latter being favoured at high MeCN concentration (see the ESI, §IV † ). 24 This result was confirmed by DFT calculations: 25 while the formation of c3 is predicted to be the most exergonic process, both the formation of c2 (formation energy of 4.8 kcal mol −1 higher) and c4 (formation energy of only 1.1 kcal mol −1 higher) may be accessible as a function of the MeCN concentration (see ESI, §V † ).…”